We have recently observed a potentially protective effect of fish oil intake on the development of chronic obstructive pulmonary disease (COPD) using validated, questionnaire-based definitions of fish oil intake and COPD in the Nurses' Health Study. The primary aims of the current application are to replicate this promising finding with more precise measures of exposures and outcomes and to investigate potential molecular and genetic intermediaries in a population of 557 older, current and former smokers. The main hypotheses are: 1) dietary fish intake and n-3 PUFA levels are inversely associated with longitudinal lung function decline and CT lung density; 2) n-3 PUFA levels are inversely associated with biological intermediaries, such as leukotriene (LT)-B4, tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and soluble adhesion molecules, and these intermediaries are on the causal pathway between n-3 PUFA levels and lung function decline; 3) related genes variants, such as those in genes coding for TNF-alpha, ICAM-1 and nitric oxide synthase (NOS) isoforms, identify individuals at higher risk of lung function decline. Baseline questionnaire, spirometry, and chest CT data and blood specimens have been collected for 557 participants, and one-year follow-up visits for questionnaire, spirometry and chest CT measures are currently ongoing. We propose to study the above hypotheses in this cohort of older, former and current smokers by extending follow-up for an additional four years; the total of six measures would yield adequate power to examine the important relationships between fish intake, n-3 polyunsaturated fatty acids (PUFA), inflammatory mediators, related gene variants and longitudinal lung function. Use of this existing cohort with previously collected blood samples will provide relatively cost-effective results about this potentially promising and safe therapy for COPD.